“This study heralds the dawn of a new age, with the opportunity to treat CLL patients with refractory disease and to treat them much more safely,” stated Richard R. Furman, MD, Richard A. Stratton Associate Professor in Hematology and Oncology at Weill Cornell Medical College, New York. “Idelalisib represents an important addition to the armamentarium for patients living with this life-threatening disease.”

Idelalisib is a targeted, highly selective, orally administered inhibitor of the delta isoform of the PI3K enzyme, which is found exclusively in hematopoietic cells and is essential to survival of CLL cells. The drug inhibits cell proliferation and induces apoptosis of CLL cells. It also inhibits homing and retention of CLL cells in lymphoid tissues, reducing cell survival, Dr. Furman explained at a late-breaking abstract session during the 2013 American Society of Hematology (ASH) Annual Meeting in New Orleans. These properties of idelalisib explain the rapid and dramatic reduction in lymphadenopathy seen with this drug, before lymphocyte counts are reduced, he said.

Study 116

Study 116 was a randomized controlled, double-blind study conducted in the United States and Europe investigating the benefit of rituximab plus idelalisib compared with rituximab plus placebo. Eligible patients were considered unfit for chemotherapy, as defined by a Cumulative Illness Rating Scale (CIRS) score > 6, creatinine clearance < 60 mL/min, or myelosuppression secondary to prior chemotherapy.

A total of 220 patients were randomly assigned between the two arms. At baseline, both treatment arms were well balanced. The median number of prior therapies was three in each arm, 91% in the idelalisib arm and 88% in the placebo arm had received prior rituximab, and time since diagnosis was 7.8 and 8.6 years, respectively.

All patients received rituximab at 375 mg/m2, followed by 500 mg/m2 every 2 weeks for four doses, and then every 4 weeks for three doses, for a total of eight doses over 6 months. Idelalisib was administered at a dose of 150 mg twice daily. Patients continued on either idelalisib or placebo until disease progression, at which point they were given idelalisib at 150 mg twice daily in addition to their current therapy. Thus, patients initially on placebo received idelalisib at 150 mg plus placebo twice daily and patients initially on idelalisib at 150 mg received idelalisib at 300 mg twice daily.

The study was stopped early based on a prespecified interim analysis by an independent monitoring committee showing a highly statistically significant effect of idelalisib/rituximab on progression-free survival, the primary endpoint. Median progression-free survival was not reached in the idelalisib/rituximab arm vs 5.5 months in the rituximab/placebo arm (P < .0001), representing an 85% improved likelihood of progression-free survival with the novel agent. For all prespecified subgroups, progression-free survival favored idelalisib/rituximab over placebo/rituximab.

Overall survival also favored idelalisib/rituximab over rituximab/placebo (P = .018). A decrease in lymphadenopathy, based upon “nodal response” (which required a > 50% reduction), was seen in 93% of the idelalisib/rituximab arm vs 4% of the placebo/rituximab arm.

Based on these findings, idelalisib was granted Breakthrough Therapy designation for CLL by the U.S. Food and Drug Administration.

“With drugs like idelalisib, we have a great opportunity to eliminate chemotherapy from the treatment paradigm. The focus has always been on eliminating chemotherapy for patients who are unfit and likely to suffer toxicities. My hope is that with these novel agents (tyrosine kinase inhibitors), even medically fit patients will be able to avoid chemotherapy and its toxicities, making long-term survival a reality,” Dr. Furman commented. ■

The findings, published in the online Early Edition of the Proceedings of the National Academy of Sciences on March 25, 2013 represent a potential new therapy for treating at least some patients with CLL, the most common type of blood cancer in the United States.

CLL cells express high levels of a cell-surface glycoprotein receptor called CD44. Principal investigator Thomas Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues identified a monoclonal antibody called RG7356 that specifically targeted CD44 and was directly toxic to cancer cells, but had little effect on normal B cells.

Moreover, they found RG7356 induced CLL cells that expressed the protein ZAP-70 to undergo apoptosis or programmed cell death. Roughly half of CLL patients have leukemia cells that express ZAP-70. Such patients typically have a more aggressive form of the disease than patients with CLL cells that do not express that specific protein.

Previous research by Kipps and others has shown that CLL cells routinely undergo spontaneous or drug-induced cell death when removed from the body and cultured in the laboratory. They found that CLL cells receive survival signals from surrounding non-tumor cells that are present in the lymph nodes and bone marrow of patients with CLL. One of these survival signals appears to be transmitted through CD44. However, when CD44 is bound by the RG7356 monoclonal antibody, it seems to instead convey a death signal to the leukemia cell.

"By targeting CD44, it may be possible to kill CLL cells regardless of whether there are sufficient numbers of so-called 'effector cells,' which ordinarily are required by other monoclonal antibodies to kill tumor cells," said Kipps. "We plan to initiate clinical trials using this humanized anti-CD44 monoclonal antibody in the not-too-distant future."

(Sep. 28, 2011) — Pre-clinical research has generated some very promising findings about a prototype drug for the treatment of chronic lymphocytic leukemia (CLL). The findings, from work carried out by scientists at NUI Galway, are published in this month's Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.

The research introduced a molecule, or prototype drug, to blood samples from patients with the type of blood cancer known as CLL. The findings indicated that the prototype drug kills leukemia cells circulating in the blood, including cells with features often associated with chemotherapy resistance. Additionally, it was found that the molecule also has the potential to target dividing leukemia cells within lymph nodes. With current standard treatment, these cells can act as a reservoir of resistant cells, which can then give rise to relapse.

For the last two and half years, NUI Galway's Professor Corrado Santocanale, along with Professor Michael O'Dwyer and Professor Afshin Samali, among others, have been researching this molecule 'PHA-767491' for treating CLL.

La molécule s'appelle PHA-767491.

According to Professor Corrado Santocanale, who works in NUI Galway's National Centre for Biomedical Engineering (NCBES) and in the Centre for Chromosome Biology (CCB): "Generally, the prognosis for patients diagnosed with CLL, one of the commonest types of blood cancer, is not as positive as we would like. However these laboratory results provide some hope for the future, especially as related trials with patients are already underway."

Ces résultats de laboratoire fournissent de l'espoir.

The molecule is the parent compound of a drug now being tested in a phase one clinical trial led by Professor Michael O'Dwyer at the HRB Clinical Research Facility at NUI Galway. The success of the laboratory research was an important factor in developing the clinical trial.

Une molécule parente est testé en phase I

Frank Giles, Professor of Cancer Therapeutics and Director of the HRB Clinical Research Facility at NUI Galway, commented: "Enormous progress in anti-cancer therapy is being made as pre-clinical identification of an optimal target, the development of small molecule that modulate the target, and the conduct of early phase human studies, are becoming a seamless process. The conduct of these early studies is a top priority for our NUI Galway CRF and demonstrates Ireland's increasing strength in this critical biomedical sector."

Pre-clinical cancer biology research at NUI Galway encompasses multidisciplinary research clusters who are working to understand the underlying cellular and molecular mechanisms responsible for the initiation and progression of cancer, and to develop new and better cancer therapies. The University also has a strong translational and clinical research programme with the objective of translating research discoveries into improved patient care.

Researchers at the University of California, San Diego (UCSD) and the Moores UCSD Cancer Center have discovered what could be a novel drug target for an often difficult-to-treat form of leukemia. The investigators have identified a unique "signature" or pattern of a specific family of enzymes in patients with chronic lymphocytic leukemia (CLL), the most common form of adult leukemia.

Paul Insel, M.D., professor of pharmacology and medicine at the UC San Diego School of Medicine and his co-workers compared white blood cells in patients with CLL to those of healthy adults. They found that one form of the group of enzymes, collectively known as cyclic nucleotide phosphodiesterases, was 10 times higher in CLL patients than in normal individuals. The specific type of enzyme, phosphodiesterase 7B (PDE7B), controls the levels of cyclic AMP (cAMP), a molecule that can promote programmed cell death, a process that is defective in CLL. The team reports its findings this week in the Proceedings of the National Academy of Sciences.

The scientists subsequently tested the effects of drugs that blocked PDE7B in CLL cells, and found that this raised cAMP levels and caused CLL cells to undergo cell death. He explained that since PDE7B degrades cAMP, blocking PDE7B in essence takes the clamp off of programmed cell death, enabling CLL cells to die.

"PDE7B is thus a new drug target for CLL," he said. "We have preliminary data from patient samples studied in the laboratory showing that we can increase the killing of CLL cells even more if we block PDE7B and also add other drugs used to treat CLL."He noted that a test for PDE7B might also potentially be used as a way to detect CLL, though this has yet to be proven. CLL, which usually strikes adults over age 35, has two major forms. One form progresses slowly, with few symptoms for years, and can be difficult to detect. The other form is more aggressive and dangerous. No one knows what makes one form different from the other. Current therapies have limited effectiveness, especially once the disease is in its aggressive phase.The researchers are planning to screen potential drugs to treat CLL based on the PDE7B-cAMP connection. They are also exploring other potential treatment strategies to increase cAMP or disrupt its breakdown.

"We think that CLL cells may have found ways to help keep themselves alive by preventing cAMP from increasing," Insel said. "This paper provides a validation of the importance of the cAMP pathway as a target for drugs that might be used to treat CLL."